The investigators request funds for a Phase I SBIR to develop targeted delivery methods for anti-retroviral drugs to macrophages. Eventually, coated microparticles which contain lipid-bearing prodrugs will be ingested by macrophages in vitro, the microparticle coating will be hydrolytically unstable, and the lipid moieties will be linked via a HIV or CMV viral protease-digestible peptide linkage. The lipid moiety will be ceramide-based to facilitate subcellular localization of the lipid-linked prodrug to the virus-rich Golgi region within the macrophage. If the macrophages are infected with HIV or CMV, the respective viral proteases will cleave the lipid moiety from the prodrug and release the active form of the drug at the site of infection. The Phase I studies proposed in the present grant will use a model dye-peptide linkage and in vitro simulation. Release of the fluorescent dye from the microparticles following incubation with HIV or CMV proteases will provide proof of concept and pave the way for Phase II followup. Aim 1 will develop synthetic procedures for incorporation of viral protease-specific, cleavable bonds into drug attachment chemistries as well as HPLC procedures for analysis of the lipid-dye-complexes. Initially, ceramide-polypeptide(HIV)-dye and ceramide-polypeptide(CMV)-dye complexes will be prepared. Aim 2 will determine the rate of release of the model dye from the lipid-dye complex when incubated with HIV and CMV proteases. Recombinant HIV protease will be purchased, rhCMV protease will be provided by Dr. Scott Wong (ORPC) under subcontract. Both of these aims are preparatory to Aim 3 in which the lipid-dye-complexes will be used to coat microparticles of varying sizes. Finally, in Aim 4, the investigators will determine the best properties of the hydrolytically unstable coating for the microparticles to preclude premature dye release prior to macrophage ingestion. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE